Hemiacetal compounds and the applications thereof

ABSTRACT

The invention relates to compounds of formula: ##STR1## in which m, n, p and q are equal to 0 or 1, p being different from q and the sum m+n+p+q being equal to 2, A denotes a nonionic chain arrangement chosen from the groups: 
     
         --C.sub.2 H.sub.4 O--.sub.r 
    
     and/or 
     
         --C.sub.3 H.sub.5 (OH)O--.sub.s, 
    
     in which r denotes a number which can assume all integral values between 0 and 5 or a statistical average value between 0 and 20, 
     s denotes a number which can assume all integral values between 0 and 5 or a statistical average value between 0 and 10, 
     u is equal to 0 or 1, with the restriction that when u=0, s and r are also zero, 
     R denotes 
     (i) a linear or branched hydrocarbon radical which has 1 to 32 carbon atoms and can contain one or more oxygen atoms in the chain or bear one or more OH groups or 
     (ii) a (C 8  -C 18  alkyl)phenyl radical. 
     These compounds can be used for preparing stable chemical compounds, for conveying active substances or for forming vesicles.

This is a divisional of application Ser. No. 874,006 filed June 13, 1986now U.S. Pat. No. 4,827,003.

The invention relates to new compounds bearing a cyclic hemiacetalgroup, the preparation thereof and their use in organic synthesis forpreparing well defined chemical compounds, or in mixtures, or inchemical technology in various industries such as cosmetics,pharmaceuticals, medical diagnosis, textiles, agriculture, and the like.

In the chemical industry, it is important to be able to have availablecompounds which are both reactive and stable.

The Applicant has discovered new compounds, forming the subject of thepresent invention, which possess these advantages and are reactivetowards a large number of chemical compounds or various substrates(fibres, resins, powders, sheets, etc.) bearing amine, thiol, hydroxyl,etc., groups.

These compounds can be used for preparing stable chemical compounds, oralternatively be employed to convey "active substances" with which theyreact, forming a labile covalent bond, thereby enabling these activesubstances to be released under special conditions. Some of thesecompounds can be used to form vesicles in an aqueous medium.

The products according to the invention are essentially characterized inthat they correspond to the formula: ##STR2## in which: m, n, p and qare equal to 0 or 1, being different from q and the sum i m+n+p+q=2,

A denotes a nonionic chain arrangement chosen from the groups --C₂ H₄O--_(r) and/or --C₃ H₅ (OH)O--_(s),

r denotes a number which can assume all integral values between 0 and 5or a statistical average value between 0 and 20,

s denotes a number which can assume all integral values between 0 and 5or a statistical average value between 0 and 10,

u is equal to 0 or 1, with the restriction that when u is zero, s and rare also zero,

R denotes:

(i) a linear or branched hydrocarbon radical which contains from 1 to 32carbon atoms and can contain one or more oxygen atoms in the chain orbear one or more hydroxyl groups,

(ii) an alkylphenyl radical in which the alkyl radical contains 8 to 18carbon atoms.

The group --C₃ H₅ (OH)O-- denotes the following 3 structures: ##STR3##

Two compounds are regarded as isomers when the indices r and/or s havethe same integral value and in which:

either the groups --C₃ H₅ (OH)O-- described above are different instructure,

or the heterocyclic systems containing the hemiacetal group of formula(I) are different in structure,

or both of these together.

The mixtures of homologous compounds, that is to say the compoundshaving various degrees of polymerization in which r and/or s have astatistical average value, or possibly having different hydrocarbonchain lengths, also form part of the invention.

The hemiacetal derivatives of the invention are obtained by oxidationwith periodic acid, or its sodium salt (NaIO₄), of (poly)glycerol etherscontaining a terminal 2,3-dihydroxypropyl ether group and, in addition,a third hydroxyl group in the β- or γ-position to the ether group.

The (poly)glycerol ethers which can be used in the process according tothe invention can be represented by the formulae below: ##STR4## inwhich R and A have the meanings stated above.

The preparation of the hemiacetals according to the invention can beillustrated schematically by the following reactions: ##STR5##

The mixtures of polyglycerol ethers which are used in the processaccording to the invention can contain small proportions of monoglycerolethers not possessing the third OH group in the β- or γ-position to theether group. These compounds are oxidized to an ether of ethanal, thepresence of which is not detrimental, and they can be removed ifnecessary.

The polyglycerol ethers required for the synthesis of the products ofthe invention are prepared according to known processes. They can beprepared, in particular, from alcohols ROH or (poly)ethoxylated alcoholsof formula R--O--(C₂ H₄ O)_(r) in which R and r have the meanings statedabove, according to the following processes:

On an alcohol, a mixture of alcohols, a (poly)ethoxylated alcohol or amixture of polyethoxylated alcohols, there is performed a (poly)additionof:

either epichlorohydrin, followed by hydrolysis, as described in FrenchPatents Nos. 1,477,048 and 2,465,780;

or tert-butyl glycidyl ether, followed by hydrolysis, as described inFrench Patent No. 2,087,785;

or allyl glycidyl ether, followed by purification to isolate themonoaddition product and finally hydroxylation, as described in FrenchPatent No. 1,484,723.

The glycerol ethers of formula (IID) and (IIE) are obtained according toconventional means, for example by addition of glycerin or itsderivatives to an epoxide.

The hemiacetals are prepared from the (poly)glycerol ethers whichcorrespond to the definitions given above.

The (poly)glycerol ethers may be used:

either in the state of a single pure product,

or in the state of a mixture of isomers,

or in the state of a mixture of isomers and homologues.

The pure products, isomers and homologues are defined as stated above.

The pure hemiacetals are either obtained from the pure (poly)glycerolethers, or are isolated from mixtures by distillation, preparative HPLC(high pressure liquid chromatography) or any other process.

The oxidation reaction of the (poly)glycerol ethers is performedcarrying out prior solubilization of the starting compounds in water orin an alcohol such as methanol, ethanol or isopropanol, in proportionsvarying from 5 to 30% of active material. To this solution, metaperiodicacid or its sodium salt, to which has been added its own weight ofwater, is added at a temperature of between 10° and 80° C., andpreferably between 20° and 40° C., in the proportion of 1 to 1.1 moleper terminal --CHOH--CH₂ OH group of compound(s) IIA, IIB, IIC, IID orIIE. Agitation is maintained for a period ranging from rather less thanan hour to several hours. The excess periodic acid and the iodic acidformed are removed either by washing with water or by gel filtration orfiltration on silica.

The hemiacetal compounds according to the present invention arecharacterized especially by their reactivity towards alcohols, amines,thiols, basic amino acids, proteins, polymers bearing primary aminegroups, and the like.

They can react with primary amines such as (C₁ -C₁₈)alkylamines,arylalkylamines such as benzylamine, and primary amines having alcoholgroup(s), especially monoethanolamine, diglycolamine,tris(hydroxymethyl)aminomethane, 2-amino-2-methyl-1,3-propanediol andglucamine.

The reaction with amines is conducted at room temperature in a solventsuch as water or methanol. A Schiff's base is obtained, which is reducedby reducing agents such as NaBH₄ or NaBH₃ CN, and this reaction can leadto compounds represented by the following general formulae:

    R--O--A--C.sub.3 H.sub.5 (OH)--OCH.sub.2 --CH.sub.2 --NHR.sub.1(IV)

when the starting hemiacetal has the formula IA, IB or IC, or

    R--CHOH--CH.sub.2 --O--CH.sub.2 --CH.sub.2 NHR.sub.1       (IV')

when the starting hemiacetal has the formula ID, in which R and A havethe same meaning as above and R₁ denotes the primary amine residue.

The hemiacetals according to the invention can also be reacted withprimary/tertiary diamines such as dimethylaminoethylamine,dimethylaminopropylamine, diethylaminoethylamine ordiethylaminopropylamine.

The hemiacetals defined above also react with natural or syntheticpolymers bearing primary amine groups and having a molecular weight ofless than or equal to 1,000,000, such as chitosan, polyethyleneiminesand polyvinylamines.

Other compounds having an amine group which are capable of reacting withthe hemiacetals are chosen from amino acids such as lysine, proteinssuch as, for example, trypsin, glutathione, polylysine, orimmunoglobulins of the IgG type or other antibodies.

The hemiacetals according to the invention can also be made to reactwith mercaptans R₂ SH, where R₂ denotes a C₁ -C₁₈ alkyl radical or a C₁-C₁₈ mono- or polyhydroxalkyl radical such as, for example, thioethanolor thioglycerol. Sulphur amino acids R₂ --SH, where R₂ denotes the aminoacid residue, such as, for example, cisteine, can also be reacted.

In this case, the reaction is performed at between 30° and 70° C. insolvents such as methanol or ethanol, and is catalysed by hydrochloricacid. In this case, depending on the proportion of the reagents, it ispossible to obtain thiohemiacetals represented by the general formula:##STR6## in which R, A, m, n, p, q and u have the meanings stated inconnection with the formula (I) and R₂ denotes the residue of the thiol.

The reaction with the abovementioned thiols can also lead todithioacetals represented by the formulae:

    R--O--A--C.sub.3 H.sub.5 (OH)CH.sub.2 --CH(SR.sub.2).sub.2 (VI)

when the starting hemiacetal has the formula IA, IB or IC, or

    R--CHOH--CH.sub.2 --O--CH.sub.2 --CH(SR.sub.2).sub.2       (VI')

when the starting hemiacetal has the formula ID, in which formulae R andA have the same meaning as stated above and R₂ denotes the residue ofthe thiol.

The hemiacetals of formula (I) can also react with linear or branchedalcohols of formula R₃ OH, where R₃ denotes a C₁ -C₁₈ hydrocarbonradical.

In this case, the reaction is performed at a temperature of between 30°and 70° C. and is catalysed by acids such as sulphuric acid or Lewisacids such as BF₃. In this case, acetals are obtained corresponding tothe formula: ##STR7## in which R, A, m, n, p, q and u have the meaningsstated above and R₃ denotes the residue of the alcohol.

As alcohols, C₁ -C₁₈ monohydric alcohols such as, for example, ethanol,butanol or dodecanol may be mentioned.

The hemiacetals of formula (I) can also react with phenols oralkylphenols of formula R₄ OH, where R₄ denotes an optionallysubstituted phenyl radical or an alkylphenyl radical, under conditionssimilar to those described for the reaction with alcohols. Acetals areobtained of formula VIII: ##STR8## in which R, A, m, n, p, q and u havethe meanings stated above and R₄ denotes the residue of the phenol. Asphenols, phenol, resorcinol, octylphenol and nonylphenol may bementioned.

The compounds according to the invention can also undergo a reductionreaction, such as with, for example, sodium borohydride (NaBH₄), to leadto alcohols corresponding to the formulae:

    R--O--A--C.sub.3 H.sub.5 (OH)--O--CH.sub.2 --CH.sub.2 OH   (IX)

when the starting hemiacetal has the formula IA, IB or IC, or

    R--CHOH--CH.sub.2 --O--CH.sub.2 --CH.sub.2 OH              (IX')

when the starting hemiacetal has the formula ID.

The compounds resulting from the various reactions described above, andrepresented in particular by the formulae IV, IV', V, VI, VI', VII,VIII, IX and IX', are new and constitute a further subject of theinvention.

These compounds or mixtures of compounds can find various applications.

When the hemiacetals which are the subject of the invention bear a longaliphatic chain, for example containing at least 12 carbon atoms, theypossess surfactant properties and can be dispersable or soluble in waterdepending on the values of r and s. Among the products which aredispersable in water, some possess, in particular, the property offorming vesicles or liposomes.

These products generally take the form of spherules dispersed in anaqueous medium, and consist of multimolecular layers, and preferably ofbimolecular layers having an approximate thickness of 30 to 100 Å [seein particular the paper by Bangham, Standish and Watkins, J. Mol. Biol.,13, 238 (1965)]. For the sake of simplicity, the term liposome will beused to designate this type of product.

The liposomes can be obtained, in particular, according to the processdescribed in the Applicant's French Patent No. 2,315,291, according towhich a dispersion of spherules consisting of organized molecular layersenclosing an aqueous phase is prepared by bringing into contact, on theone hand a hemiacetal or a mixture of hemiacetals of formula (I), inwhich R denotes a group preferably having at least 12 carbon atoms, andon the other hand the aqueous phase to be encapsulated in the saidspherules, agitating to ensure mixing and obtain a lamellar phase, thenadding a dispersion liquid in an amount greater than the amount oflamellar phase obtained and shaking vigorously for a period varyingbetween 15 minutes and 3 hours approximately.

The ratio by weight between the aqueous phase to be encapsulated,brought into contact with the hemiacetals according to the invention,and the hemiacetals forming the lamellar phase is between approximately0.1 and approximately 3.

The ratio by weight of the dispersion phase, which is added, to thelamellar phase, which is dispersed, is preferably between approximately2 and approximately 100, the dispersion phase and the aqueous phase tobe encapsulated preferably being isoosmotic.

The dispersion phase is an aqueous solution containing, whereappropriate, active substances.

The agitation is carried out by means of a shaker and the process can beperformed at room temperature or at a higher temperature, depending onthe nature of the hemiacetal. It is also possible to subject thedispersion of spherules to ultrasound treatment when it is desired toobtain liposomes having a mean diameter of less than 1000 Å.

Another preparation process can consist in using the process known asREV (reverse-phase evaporation vesicle), described in Proc. Natl. Acad.Sci. USA, Vol. 75 No. 9 p. 4194-4198 (1978) by Szoka andPapahadjopoulos.

Various additives can be incorporated for the purpose of modifying thepermeability or the surface charge of the liposomes.

To this end, mention may be made of long-chain alcohols and diols,sterols, for example cholesterol, long-chain amines and their quaternaryammonium derivatives, dihydroxylamines, polyoxyethylenated fatty amines,long-chain esters of amino alcohols, their salts and quaternary ammoniumderivatives, phosphoric acid esters of fatty alcohols, alkyl sulphatesor other lipids of the type defined in French Patent No. 2,315,991 andmore especially lipids containing a saturated or unsaturated, branchedor linear lipophilic chain from 12 to 30 carbon atoms long, such as, forexample, oleic, lanolic, tetradecyl, hexadecyl, isostearyl, lauric oralkylphenyl chains. The hydrophilic group of these lipids can be anionic or nonionic group. By way of nonionic groups, groups derived frompolyethylene glycol may be chosen. When the hydrophilic group of thelipid which forms the lamellar phase is an ionic group, an amphoteric,anionic or cationic compound can be chosen, for example, as lipidshaving a hydrophilic group. Polyglycerol ethers such as those describedin French Patent Nos. 1,477,048, 2,091,516, 2,465,780 and 482,128 canthus be used.

As is well known, the aqueous phase to be encapsulated can be water oran aqueous solution of active products such as, for example, substanceshaving pharmaceutical, foodstuff or nutrient value, or substances havingcosmetic activity.

As regards substances having cosmetic activity, it is possible, forexample, to use products intended for skin care and hair care such as,for example, humectants such as glycerin, sorbitol, pentaerythritol,inositol, pyrrolidonecarboxylic acid and its salts; artificial suntanagents such as dihydroxyacetone, erythrulose, glyceraldehyde,γ-dialdehydes such as tartaraldehyde, optionally combined withcolourings; water-soluble anti-sunburn agents, antiperspirants,deodorants, astringents, freshening-up products, tonics, healingproducts, keratolytics, depilatories; scented waters; extracts of animaland plant tissues such as proteins, polysaccharides, amniotic fluid;water-soluble colourings, antidandruff agents, antiseborrheic agents,oxidizing agents such as bleaching agents, for example hydrogenperoxide, and reducing agents such as thioglycolic acid and its salts.

As active pharmaceutical substances, vitamins, hormones, enzymes such assuperoxide dismutase, vaccines, anti-inflammatories such ashydrocortisone, antibiotics, bactericides, cytotoxic agents orantitumour agents may be mentioned.

A subject of the invention consists of liposomes or spherules indispersion, obtained using at least one hemiacetal of formula I andhaving a diameter of between 0.1μ and 5μ.

An especially advantageous application of the liposomes defined above isthe reaction at their surface with compounds or products bearingalcohol, thiol or amine groups, and formation of a covalent bond.

In the case of reactions with compounds or products bearing aminegroups, the reaction may be followed by reduction with reducing agentssuch as NaBH₄ and NaBH₃ CN to form a covalent bond between the productbearing amine groups and the liposome.

Usable products bearing amine groups can be proteins preferablycontaining lysyl residues, especially at least 20 lysyl radicals. Tothis end, immunoglobulins such as IgG may be mentioned.

An advantageous application of this type of reaction is the coupling ofspecific antibodies or monoclonal antibodies with liposomes containingcytotoxic substances or substances capable of modifying the behaviour ofa cell. The antibodies are then capable of specifically directing theliposomes and their contents to the target cells.

Another application is in methods of medical diagnosis such as, forexample, in a method for visualizing haemagglutination in thedetermination of Rhesus factor by means of an antibody-antigeninteraction.

The examples which follow are intended to illustrate the inventionwithout thereby being limitative in nature.

EXAMPLE 1

A mixture of polyhydroxypropylene ether compounds: ##STR9## n having anaverage statistical value of approximately 3, is prepared according toFrench Patent No. 1,477,048.

232 g of the abovementioned mixture are solubilized in 2.5 of methanol.126 g of metaperiodic acid, to which its own weight of water has beenadded, is added to this solution in the course of half an hour and atroom temperature. The reaction mixture is agitated for 3 hours. 2 litersof water are then added.

Copious precipitation of a white solid is observed.

Is is collected by centrifugation and then washed three times with 200cc of boiling water.

After being dried, 200 g of a product of waxy appearance, very slightlytinted yellow and melting below 50° C., are isolated.

This product is a statistical mixture of hemiacetal derivatives. Thepure compounds are isolated by subjecting the above mixture topreparative high pressure liquid chromatography (HPLC).

The chromatography conditions are as follows:

Sample: 67 g solubilized in 100 cc of dichloromethane.

Phase: 1 kg of Merck 60 H Kieselgel (silica gel 60 H, sold by Merck).

Compression of the phase: 9 bars.

Eluent: dichloromethane/methanol=85:15.

Elution pressure: 9 bars.

The following are isolated: 26 g, 13 g and 6 g, respectively, of thecompounds I, II and III.

Compound I ##STR10##

White solid of melting point 70° C.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            70.34     70.07    H            11.81     11.76    ______________________________________

IR: Stretching C--O 1150, 1120 and 1065 cm⁻¹ ; absence of C═O band

The ¹³ C NMR spectrum accords with the structure of the compound I.

Compound II ##STR11##

White solid of melting point 56° C.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            66.63     66.7    H            11.18     11.2    ______________________________________

The ¹³ C NMR spectrum accords with the above structure. Massspectroscopy on silylated derivative OH= OSi(CH₃)₃ M⁺ -15=561.

Compound III ##STR12##

White solid of melting point 50° C.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            64        64.41    H            10.74     10.8    ______________________________________

EXAMPLE 2

To 521 g (2.15 moles) of molten hexadecanol, there are added 18.38 g ofa solution of sodium methylate in methanol (5.82 meq/g). 164 g (1.43moles) of allyl glycidyl ether are then added at 150° C. and in thecourse of 1 h 30 min, and agitation is maintained for a further 1 hour.The product is then washed with boiling water until neutral, and thendistilled at 0.01 mm Hg. 128 g are collected of a liquid fraction whichdistils at 172° C. and which consists of a single product:

    C.sub.16 H.sub.33 OCH.sub.2 CHOHCH.sub.2 OCH.sub.2 CH═CH.sub.2

This compound is subjected to hydroxylation as described in FrenchPatent No. 1,531,010, to obtain the derivative:

    C.sub.16 H.sub.33 OCH.sub.2 CHOHCH.sub.2 OCH.sub.2 CHOHCH.sub.2 OH

126 g of the above compound are dissolved in 2 liters of methanol. 82 gof metaperiodic acid, to which its own weight of water has been addedare added to this solution in the course of half an hour and at roomtemperature.

The reaction mixture is agitated for 3 hours. The formation of aprecipitate is observed. To enhance the precipitation, 2 liters of waterare added. The solid is drained, taken up with 2 liters of chloroformand washed with 3 times 200 cc of water. After the product is dried,there are collected 104 g of a compound of formula: ##STR13##

This is a white solid of melting point 92° C.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            70.34     70.28    H            11.81     11.8    ______________________________________

The ¹³ C NMR spectrum accords with the above structure.

EXAMPLE 3

1.8 cm³ of BF₃.Et₂ O is added to 403 g (1.66 mol) of molten hexadecanol,and the mixture is brought to 70° C. At this temperature, 190 g (1.66mol) of allyl glycidyl ether are added in the course of 1 hour, andheating is maintained for 1 hour. The mixture is washed several timeswith boiling water and then distilled at 0.01 mm Hg. 228 g are collectedof a fraction which distils at 175° C. and which contains the twocompounds: ##STR14##

This mixture is subjected to hydroxylation as described in French PatentNo. 1,531,010, to obtain the derivatives: ##STR15##

50 g of the above mixture are dissolved in 700 cm³ of methanol. Thesolution is treated under the same conditions as in Example 2 with 31 gof metaperiodic acid to which its own weight of water has been added.After 3 hours' agitation, 700 cm³ of water are added. The solid formedis drained, taken up with 700 cm³ of chloroform and washed with 3 times75 cm³ of water. After being dried, 40 g of a mixture of the followingcompounds are collected: ##STR16##

This is a white solid of melting point 83° C.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            70.34     70.62    H            11.81     11.85    ______________________________________

In gas chromatography, this mixture shows two peaks, the more abundantof which is superposed with the peak of the compound of Example 2.

Mass spectroscopy shows that the two compounds have indeed the samemass: M⁺ -18=340.

IR spectroscopy shows the absence of the characteristic aldehyde band.

EXAMPLE 4

1.79 g (0.005 mol) of the hemiacetal (I) prepared according to Example 1is dissolved in 25 cm³ of absolute ethanol. 3 cm³ of ethanol saturatedwith HCl are added to this solution, followed by 0.9 g (0.01 mol) ofbutylmercaptan. The mixture is agitated for 10 hours at roomtemperature. It is evaporated to dryness.

The solid is taken up with hexane and washed several times with water.The mixture obtained is subjected to preparative HPLC (same conditionsas in Example 1, but with dichloromethane as eluent).

On the one hand, 0.3 g is isolated of a thioacetal of formula: ##STR17##The ¹³ C NMR spectrum accords with this structure.

On the other hand, 0.5 g is isolated of a dithioacetal of formula:##STR18## The ¹³ C NMR spectrum accords with this structure.

EXAMPLE 5

3.58 g (0.01 mol) of hemiacetal (I) prepared according to Example 1 aredissolved in 50 cm³ of a solution of HCl in methanol (2.6N). 1.95 g(0.025 mol) of mercaptoethanol dissolved in 30 cm³ of methanol is addedto this solution. The solution is heated for 6 hours at 50° C. and thenevaporated to dryness. The mixture is subjected to preparative HPLC(same conditions as in Example 1, but with the eluentdichloromethane/isopropanol, 90:10).

1.5 g of a pasty solid is isolated. This is the dithioacetal: ##STR19##Le ¹³ C NMR spectrum accords with this structure.

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            60.48     60.57    H            10.48     10.5    S            12.9      12.66    ______________________________________

EXAMPLE 6

2 g (0.006 mol) of hemiacetal (I) prepared according to Example 1 aredissolved in 55 cm³ of methanol. 0.41 g (0.006 mol) of butylamine isadded to this solution. The mixture is agitated at room temperature. Aprecipitation is observed and this becomes enhanced with the passage oftime. After 4 hours' agitation at room temperature, 1.85 g of a whitesolid is isolated by filtration.

1 g of this solid is redissolved in 30 cm³ of methanol. 0.092 g (0.0024mol) of sodium borohydride is added to this solution and the mixture isagitated for 3 hours at room temperature. 1 drop of acetic acid is thenadded. The mixture is evaporated to dryness. The residue is taken upwith dichloromethane and the solution washed with water.

After evaporation of the organic phase, the solid is redissolved inether to which a few cm³ of ether saturated with HCl are added.

By precipitation, 0.7 g is isolated of a white solid of melting point100° C. and of formula: ##STR20## The ¹³ C NMR spectrum accords with theabove structure.

EXAMPLE 7

3.58 g (0.01 mol) of the hemiacetal (I) prepared according to Example 1are dissolved in 100 cm³ of methanol. 1 cm³ of normal sulphuric acidsolution is added to this solution, followed by 1.07 g (0.01 mol) ofbenzylamine.

The solution is agitated at room temperature. A solid precipitatesduring the reaction. After 3 hours' agitation, it is isolated byfiltration.

2.24 g of this solid are redissolved in 300 cm³ of methanol. 0.185 g ofsodium borohydride is added and agitation is maintained for 1 h 30 min.1 drop of acetic acid is then added. The mixture is evaporated todryness. The solid is taken up with dichloromethane. The organicsolution is washed with water. After evaporation of the dichloromethane,an oil is collected. This oil is redissolved in ether. A white solid isprecipitated by adding a few cm³ of ether saturated with HCl. 1.7 g of awhite solid, of melting point 105° C., is isolated.

Its acid value is 2.22 meg/g. The ¹³ C NMR spectrum accords with thefollowing structure: ##STR21##

EXAMPLE 8

2 g (0.0056 mol) of hemiacetal (I) prepared according to Example 1 aredissolved in 40 cm³ of tetrahydrofuran, followed by 2.08 g (0.011 mol)of dodecanol. 16 mg of BF₃.Et₂ O are added to this solution, which isthen brought for 8 hours to 70° C.

The solvent is evaporated off and the solid subjected to HPLC, as inExample 1 but on Lichroprep Si 60 and with the system hexane/ethylacetate (9:1) as eluent.

2 g of a white solid, of melting point 58° C., are isolated.

This is a mixture of the two isomers below: ##STR22## The ¹³ C NMRspectrum accords with the above structure.

Elementary analysis

    ______________________________________               Calculated                       Found    ______________________________________    C            74.65     74.55    H            12.92     13.01    ______________________________________

EXAMPLE 9

3 g (0.0084 mol) of hemiacetal prepared according to Example 2 aredissolved in 30 cm³ of methanol. 10 drops of H₂ SO₄ (N) added and thesolution is heated for 3 hours to 60° C. The solution is then evaporatedto dryness. The solid is taken up with dichloromethane and washed withwater. The mixture is evaporated to dryness. 2 g of solid are obtainedand this is subjected to HPLC as in Example 1, with dichloromethane aseluent. 2 fractions are isolated. One of these, of 0.3 g, contains thepure compound: ##STR23##

The other fraction, of 1.5 g, contains a mixture of the compound (I) andthe compound (II): ##STR24##

Elementary analysis:

    ______________________________________               Calculated                       Found    ______________________________________    C            70.92     70.79    H            11.90     12.01    ______________________________________

Melting point: 58° C.

Mass spectroscopy: the two compounds show the same molecular peak M⁺ -32(loss of methanol)=340

The ¹³ C NMR spectra accord with the structures of the compounds I andII.

EXAMPLE 10

1 g (0.0028 mol) of hemiacetal (I) prepared according to Example 1 isdissolved in 50 cm³ of methanol. 0.1 g (0.0026 mol) of sodiumborohydride is added to this solution. The mixture is stirred for 1 h 30min at room temperature. 1 drop of acetic acid is added.

The mixture is evaporated to dryness. The residue is taken up withdichloromethane. The mixture is washed with water. 0.87 g are isolatedof a white solid of melting point 66° C. and structure: ##STR25##confirmed by the ¹³ C NMR spectrum.

EXAMPLE 11

0.5 g (0.016 mol) of hemiacetal (II) prepared according to Example 1 isdissolved in 45 cm³ of methanol, and 0.04 g (0.0011 mol) of sodiumborohydride is then added. Agitation is maintained for 3 hours at roomtemperature. 1 drop of acetic acid is added. The mixture is evaporatedto dryness. The residue is taken up with dichloromethane and the mixturewashed with water. 0.3 g is obtained of a pasty compound melting atabout 50° C., of structure: ##STR26## confirmed by the ¹³ C NMRspectrum.

Mass spectroscopy: silylated derivative with OH=OSi(CH₃)₃ peak M⁺+H=651.

EXAMPLE 12

Preparation of a dispersion of active vesicles.

The starting materials are the following products:di(hydroxypropylenoxy) derivative ##STR27## hemiacetal II preparedaccording to Example 1: 1.188 g;

cholesterol: 2.375 g;

dicetyl phosphate: 0.25 g;

aqueous solution containing 0.02% of NaN₃ : 95 g.

Procedure

95 g of an aqueous solution of NaN₃ are added slowly and with manualagitation to the 5 g of molten lipids (60°-80° C.). The dispersionformed is made finer by ultradispersion (Polytron 20,000 rpm) followedby sonication.

The dispersion obtained, which is stable for several months, consists ofnon-flocculated mono- or multilamellar vesicles, the average diameter ofwhich, measured using a Coulter N4 counter (Coultronics), is between 100and 150 nm, and the surface potential (Zeta potential) of which,measured using a Zmeter 501 laser, is in the region of -60 mV.

Reaction of the vesicles with protein

The vesicle dispersion is diluted with a borate buffer solution (10 mMNa₂ B₄ O₇, 60 mM NaCl, 3 mM NaN₃) to a final concentration of 20 mg oflipids/ml of dispersion.

4 ml of solution of Sigma trypsin -60% pure-(20 mg/ml of buffersolution) is added to 4 ml of this dispersion in the course of 10 minwith agitation.

The mixture is adjusted to pH 9.5 by adding N NaOH and left agitated atroom temperature for approximately 2 hours. 60 μl of freshly preparedNaBH₄ solution (10% strength in the buffer) are then added [equivalentto 3.6 moles of NaBH₄ per mole of hemiacetal of formula (II)].

The mixture is agitated for 1 hour and then left standing overnight atroom temperature.

The vesicles and the free trypsin are separated by filtration on aSephadex G-200 column (sample deposition 3 ml, eluent borate buffer pH8.4, ascending elution, flow rate 0.5 ml/min).

The vesicles obtained have an average diameter of between 100 and 200 nmand contain approximately 9 mg of trypsin per g of lipids.

EXAMPLE 13

46 g (0.8 mol) of propylene oxide are added dropwise in the course of 1hour to 211 g (1.6 mol) of freshly distilled isopropylideneglycerolcontaining 0.6 ml of BF₃ etherate, the temperature being maintained at60°±5° C.

After the acidity due to the catalyst has been neutralized with 1.16 mlof sodium methylate dissolved in methanol (6 meq/g), the excessisopropylideneglycerol is distilled off under a vacuum of 30 mm ofmercury, the residue is then fractionated by distillation under a vacuumof 0.1 mm of Hg and 40 g of a colourless liquid which distils at 70°-72°C. are collected. This liquid is composed of the two isomers of theformulae below: ##STR28##

1 ml of concentrated hydrochloric acid diluted in 2 ml of water is addedto 19 g (0.1 mol) of the mixture of the above compounds dissolved in 50ml of methanol. The solution is left for 3 days at room temperature andthen concentrated under a vacuum of 25 mm Hg at 80° C.

14 g are isolated of a colourless oil showing a single spot in TLC onsilica (eluent CH₂ Cl₂ /CH₃ OH, 90:10), corresponding to a mixture ofthe two isomers: ##STR29##

A solution of 40 g of periodic acid (at HIO₄.2 H₂ O) dissolved in 150 mlof water is added to 24 g (0.16 mol) of a product obtained according tothe above procedure, dissolved in 100 ml of water, the temperature beingmaintained at 25°-30° C. during the addition; the mixture is thenagitated at room temperature for 5 hours.

The iodic acid formed is then neutralized with a suspension of 30 g ofbarium hydroxide [Ba(OH)₂.8 H₂ O] in 100 ml of water, the temperaturebeing maintained at a maximum of 35° C. The mixture is left agitated for2 hours and then filtered on No. 4 sintered glass. The filtrate isconcentrated to dryness under a vacuum of 25 mm of Hg in a bath at 50°C. The residue is taken up with 30 ml of isopropanol, the mixturefiltered again and the filtrate concentrated as above. 17 g of acolourless oil are obtained. This product is purified by preparativechromatography under pressure (Merck Silica Gel 60H, eluentdichloromethane/isopropanol: 95:5).

12 g are isolated of a colourless mobile oil which shows a single spotin TLC. By gas chromatography of the silylated mixture on a 15-mcapillary column OV 1701, four compounds are distinguished which havebeen identified as isomers by mass spectroscopy (M⁺ -H=189).

The ¹³ C NMR spectrum accords with the presence of the four isomersbelow: ##STR30##

EXAMPLE 14

A mixture of the polyhydroxypropylene ether compounds of formula:##STR31## where n has an average statistical value of 4, is preparedaccording to French Patent BF No. 2,465,780.

5 g of periodic acid (HIO₄.2H₂ O) dissolved in 6 ml of water are addedto 6.94 g (0.01 mol) of the above derivative dissolved in 400 ml ofmethanol, and the mixture is left agitated for 12 hours at roomtemperature. The solution is then brought down to 100 ml by partialevaporation of the solvent under reduced pressure. An equal amount ofwater is added at 80° C. to this concentrated solution. An oil appearsin the mixture and phase separation occurs.

After separation, the aqueous phase is washed several times withheptane. The organic extracts are combined with the oil and dried oversodium sulphate. After removal of the sodium sulphate and evaporation ofthe solvent, 6.2 g of a viscous oil are isolated.

The ¹³ C NMR spectrum accords with the structure below: ##STR32## wheren' has an average statistical value of 2.

We claim:
 1. Compound corresponding to the formula: ##STR33## in which Rdenotes (i) a linear or branched hydrocarbon radical which has 1 to 32carbon atoms and can contain one or more oxygen atoms in the chain orbear one or more OH groups or(ii) a (C₈ -C₁₈ alkyl)phenyl radical. 2.Compound corresponding to the formula: ##STR34## in which R denotes (i)a linear or branched hydrocarbon radical which has 1 to 32 carbon atomsand can contain one or more oxygen atoms in the chain or bear one ormore OH groups or(ii) a (C₈ -C₁₈ alkyl)phenyl radical.